Biomimetic Ru‐Mn Nanozyme with Cascade Catalytic Activity Attenuates Secondary Brain Injury in Intracerebral Hemorrhage

ABSTRACT Intracerebral hemorrhage (ICH) is a lethal stroke subtype with limited treatment options, largely due to secondary injury driven by oxidative stress and neuroinflammation. Here, we developed a ruthenium (Ru)‐manganese (Mn) composite nanozyme by integrating Ru nanozyme into Mn‐doped zeolitic imidazolate framework (Mn‐ZIF) to enable cascade catalytic activity for efficient ROS clearance. In vitro, Ru@Mn‐ZIF nanozyme reduced LPS‐induced microglia activation and H 2 O 2 ‐induced neuronal oxidative damage, showing stronger protective effects than Mn‐ZIF nanozyme. In vivo, both intranasal and intravenous administration of Ru@Mn‐ZIF nanozyme significantly decreased hematoma volume, preserved blood‐brain barrier integrity, suppressed inflammatory responses, and improved neurological recovery in collagenase‐ and autologous blood‐induced ICH models. Biosafety evaluation revealed no pathological or biochemical abnormalities after treatment. These findings highlight Ru@Mn‐ZIF nanozyme as a promising therapeutic strategy for mitigating secondary brain injury and improving outcomes after ICH.